FGFR3 Mutant Neoplasms

The FDA full approval allows patients who’ve progressed on standard PD-1 treatment to get J&J's Balversa. When the FDA converts an accelerated approval into a full nod, it’s typically associated with a wider label for the drug at hand. But in the case of Johnson & Johnson’s Balversa, the FDA narrowed the use of the first-in-class bladder cancer drug in two ways and expanded it in another. A full FDA approval now allows Balversa (erdafitinib) to treat locally advanced or metastatic urothelial carcinoma in patients with susceptible FGFR3 genetic alterations following at least one line of prior therapy. In a Friday announcement about the drug’s updated label, the FDA specified that Balversa shouldn’t be used in patients who are eligible for and have not received a prior PD-1/L1 therapy. Compared with Balversa’s accelerated approval from 2019, the full nod is narrower on two fronts. Under the original go-ahead, Balversa was also able to reach patients with FGFR2 alterations, and it could target post-chemo patients regardless of their eligibility for PD-1/L1 therapy. In one positive label change for J&J, while the previous nod only allowed Balversa after prior treatment with platinum-based chemotherapy, the updated approval now covers second-line patients regardless of their prior systemic therapy. That means patients who’ve progressed on standard PD-1 treatment can also get Balversa. The way J&J approached the full approval—and the way the FDA ruled—tell a cautionary tale about the FDA's close attention to patient subgroup data and overall survival findings. For the full green light, J&J only pursued the approval of Balversa in patients with FGFR3 alterations, a company spokesperson told Fierce Pharma. To support a full approval, J&J conducted the phase 3 THOR study, also known as Study BLC3001. In cohort 1 of the trial, Balversa cut the risk of death by 36% compared with chemotherapy in previously treated patients, including those treated with a PD-1/L1 inhibitor. Those who got Balversa lived a median 12.1 months versus 7.8 months for the control group. The trial was designed to enroll patients with FGFR2 and FGFR3 alterations, but it eventually didn’t have any FGFR2 representation. The real-world frequency of this disease subtype is extremely low, the J&J spokesperson said. In a statement, Daniel Suzman, M.D., a deputy director at the FDA’s oncology division, said the approval was “limited to patients with FGFR3-altered tumors only because of a lack of data confirming clinical benefit in the extremely rare population of patients with FGFR2-altered tumors.” The developments come amid a growing trend at the FDA to exclude patient subgroups in approvals, either because of low representation in clinical trials or unconvincing efficacy data. In June 2023, the FDA left out patients with high-grade B-cell lymphoma in an approval for Roche’s large B-cell lymphoma therapy Columvi, citing a “limited number of patients” in a study. As for Balversa, cohort 1 was only a part of the THOR trial. For years, Merck & Co.’s Keytruda has had a second-line bladder cancer nod and a limited first-line approval. So in cohort 2 of THOR, J&J pitted Balversa directly against Keytruda in previously treated patients who had not received a PD-1/L1 drug. And the updated Balversa label suggests the FDA was not happy with the results. In cohort 2, Balversa failed to beat Keytruda in extending patients’ lives. In fact, the J&J drug was linked to an 18% increased risk of death. “Similar” overall survival was the word investigators used when presenting the data at the 2023 European Society of Medical Oncology annual congress in October. But a small improvement on progression-free survival and a negative overall survival showing have become a precarious combination at the FDA, and Balversa was clearly no exception. J&J is looking on the bright side, stressing that patients who are eligible to receive PD-1/L1s are increasingly receiving those treatments up front. The company seems to be positioning its medicine as an option for those who still need treatment after a PD-1/L1 inhibitor. After Balversa’s accelerated approval in 2019, Merck KGaA and its former partner Pfizer won an FDA nod for their PD-L1 therapy Bavencio as a first-line maintenance therapy in bladder cancer patients who’ve responded to an initial round of chemo. And the combination of Keytruda and Astellas and Pfizer’s Padcev just won approval as a first-line treatment for bladder cancer after showing a major overall survival benefit against chemo. “Due to emerging treatment landscape, anti-PD-1s are used more and more in the earlier line setting […] and therefore, there is an unmet need for patients after progressing on anti-PD-1,” the J&J spokesperson said.

FGFR inhibitor gains FDA approval based on 40% response rate in MD Anderson-led Phase II trial FGFR inhibitor gains FDA approval based on 40% response rate in MD Anderson-led Phase II trial HOUSTON -- Treatment with the FGFR inhibitor erdafitinib in patients with metastatic bladder cancers marked by mutations in the FGFR3 gene resulted in a 40% overall response rate (ORR) and was well-tolerated, according to an international Phase II trial led by The University of Texas MD Anderson Cancer Center . The trial results, published today in the New England Journal of Medicine , led to approval of erdafitinib in April by the Food and Drug Administration (FDA), making it the first targeted therapy approved for treating patients with advanced bladder cancer. The oral targeted therapy also achieved a 59% ORR in patients for whom immunotherapy had previously failed, indicating this may be a viable option for these patients in need of alternative treatments. The findings were first reported at the 2018 American Society of Clinical Oncology Annual Meeting by principal investigator Arlene Siefker-Radtke, M.D. , professor of Genitourinary Medical Oncology . “Patients have been in desperate need for alternative strategies, especially when a large number of patients cannot tolerate the current standards of care,” said Siefker-Radtke. “We were very gratified to see a 40% response rate in patients treated on this clinical trial. Not only did it work well in patients with lymph node metastases, but also in patients with high volume and very aggressive disease.” Standard of care for these cancers is cisplatin-based chemotherapy, an aggressive regimen with significant side effects, and this has largely remained unchanged for several decades, explained Siefker-Radtke. Recently, immune checkpoint inhibitors have been approved for the treatment of advanced bladder cancer, but only 15 to 20% of patients see any benefit from these therapies, she said. “I noticed that I wasn’t seeing a great response to immune checkpoint inhibitors in my patients with FGFR3 mutations, which led me to wonder whether this would reflect a group of patients with an unmet need,” said Siefker-Radtke. “When we heard about novel agents targeting this pathway, I became quite interested in exploring them in our bladder cancer patients.” Mutations in FGFR3 are present in approximately 15 to 20% of patients with metastatic bladder cancer and up to 35% of patients with other urothelial cancers, such as those of the renal pelvis and ureter. The international trial enrolled 99 patients with metastatic or surgically unresectable urothelial cancer and verified alterations in the FGFR3 gene. Three patients in the trial had complete responses, or tumor disappearance, and 39 had percent stable disease. Median PFS was 5.5 months and median OS was 13.8 months. Among 22 patients previously treated with immunotherapy, 59% (13) had a partial or complete response. “With a response rate of over 50% in patients previously treated with immunotherapy, the data suggest treatment with erdafitinib may be preferential for patients with FGFR3 mutations. However, this is preliminary evidence, so we need additional data to confirm this finding,” said Siefker-Radtke. All patients on the trial reported side effects from the therapy, with 21% discontinuing treatment due to adverse events and 67% reporting grade 3 or 4 adverse events. The most common treatment-related side effects were stomatitis (9%), nail dystrophy (6%), and hand-foot syndrome (5%). Based on the results of the trial, the FDA granted a breakthrough therapy designation to erdafitinib in 2018 and approved the drug in April 2019 for treating patients with locally advanced or metastatic urothelial cancers with mutations in the FGFR2 or FGFR3 genes. “With the recent approval of erdafitinib for the treatment of patients with FGFR3 -mutant urothelial cancers, we now have an additional agent to add to our armamentarium,” said Siefker-Radtke. “My hope is we will be able to add this to our treatment strategy, learn how it combines with immunotherapy and how we can use the effects of this drug to improve the survival for all of our bladder cancer patients.” A Phase III trial currently is underway to evaluate the efficacy of erdafitinib relative to chemotherapy or the checkpoint blockade inhibitor pembrolizumab in patients with metastatic urothelial cancer and FGFR3 mutations. The study was funded by Janssen Research & Development, LLC. Siefker-Radtke serves on the scientific advisory committee for Janssen. A full list of collaborating researchers and their disclosures are included in the paper . About MD Anderson The University of Texas MD Anderson Cancer Center in Houston ranks as one of the world’s most respected centers focused on cancer patient care, research, education and prevention. The institution’s sole mission is to end cancer for patients and their families around the world. MD Anderson is one of only 49 comprehensive cancer centers designated by the National Cancer Institute (NCI). MD Anderson is ranked No. 1 for cancer care in U.S. News & World Report’s Best Hospitals survey. It has ranked as one of the nation’s top two hospitals for cancer care since the survey began in 1990, and has ranked first 14 times in the last 17 years. MD Anderson receives a cancer center support grant from the NCI of the National Institutes of Health (P30 CA016672).